No relevant excess prevalence of myotonic dystrophy type 2 in patients with suspected fibromyalgia syndrome.

Myotonic dystrophy type 2 (DM2) is a rare, autosomal dominant, multisystem disorder with proximal weakness, myotonia, pain and cataract as important symptoms. Given the assumed underreporting of DM2 in the Netherlands combined with the predominant role of pain in DM2 as well as in fibromyalgia syndrome (FMS), we hypothesized there will be an excess prevalence of DM2 in patients with (suspected) FMS. Our objective was to determine the prevalence of DM2 in patients with suspected FMS. A prevalence of 2% was considered a relevant excess frequency. Between November 2011 and April 2014, 398 patients with suspected FMS who had been assessed by a rheumatologist participated in this cross-sectional study. 95% of the study population was female, with a mean age of 42 years. The final ICD-9 diagnoses were collected, in 96% the diagnosis was FMS. 92% met the 2010 American College of Rheumatology (ACR) diagnostic criteria for FMS. A questionnaire including neuromuscular symptoms was completed. Creatine kinase was determined, and genetic testing for DM2 was conducted in all patients. DM2 was established in only one patient (0.25%, 95% CI 0.04-1.4%), thus disapproving our hypothesis of a relevant prevalence of 2%. Our results suggest that patients with suspected FMS should not routinely be tested for DM2.

The ability of systemic biochemical markers to reflect presence, incidence, and progression of early-stage radiographic knee and hip osteoarthritis: data from CHECK.

OBJECTIVE: To relate systemic biochemical markers of joint metabolism to presence, incidence, and progression of early-stage radiographic knee and/or hip osteoarthritis (OA). METHOD: The cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, and synovial markers sHA and sPIIINP were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of CHECK (Cohort Hip and Cohort Knee), a cohort study of early-stage symptomatic knee and/or hip OA. Knee and hip radiographs were obtained at baseline and 5-year follow-up. Presence of OA at baseline was defined as Kellgren and Lawrence (K&L) = 1 (maximum observed). Incidence of OA was defined as K&L = 0 at baseline and K&L ≥ 1 at 5-year follow-up. Progression of OA was defined as K&L = 1 at baseline and K&L ≥ 2 at 5-year follow-up. RESULTS: Data were available for 801 subjects at baseline and for 723 subjects at both baseline and 5-year follow-up. Multiple cartilage and synovial markers showed positive associations with presence and progression of knee and hip OA and with incidence of hip OA, except for negative associations of uCTX-II and sCOMP with incidence of knee OA. uCTX-II and sCOMP showed multiple interactions with other biomarkers in their associations with knee and hip OA. Bone markers were positively associated with presence of radiographic knee OA, but negatively associated with progression of radiographic hip OA. CONCLUSION: Especially metabolism in cartilage and synovial matrix appear to be of relevance in knee and hip OA. The role of bone metabolism appears to differ between knee and hip OA.

Inter-observer reliability for radiographic assessment of early osteoarthritis features: the CHECK (cohort hip and cohort knee) study.

OBJECTIVE: To calculate inter-observer reliability between four different trained readers and an experienced reader on early radiographic osteoarthritis (OA) features in our early OA cohort hip and cohort knee (CHECK) cohort. METHODS: Four readers were trained by a radiologist and experienced reader to score radiographic OA features. After this training they scored the CHECK cohort. Of the 1002 participants, 38 were scored by all readers. Five different angle radiographs (three for the knee, two for the hip) at three different time points were scored and compared. Inter-observer reliability was evaluated between each of the four trained readers and the experienced reader. Separate radiographic OA features and of overall Kellgren & Lawrence (K&L) scores. In addition, reliability of progression of radiographic was determined in K&L scores and joint space narrowing (JSN). RESULTS: For hip and knee there was substantial inter-observer reliability on overall K&L scores. In the knee, JSN was scored with fair to moderate reliability, osteophytes with moderate to nearly perfect reliability, and other features with fair to substantial reliability. In the hip, reliability ranged from substantial to nearly perfect. Moderate inter-observer reliability was found for progression of OA in both knee and hip, with slightly better reliability for progression based on K&L scores than on separate features. CONCLUSION: Good inter-observer reliability can be achieved between trained readers and an experienced reader. Although JSN in the knee is scored with lower inter-observer reliability than osteophytes, this does not seem to influence overall K&L scoring. In the hip all features showed good reliability.

Prevalence and predictors of health care use in patients with early hip or knee osteoarthritis: two-year follow-up data from the CHECK cohort.

OBJECTIVE: To describe health care utilization (HCU) and predict analgesic use and health professional (HP) contact at baseline and 2 years in individuals with early symptomatic hip and/or knee osteoarthritis (OA). DESIGN: Baseline and two-year data on HCU of the 1002 participants from the multi-centre Cohort Hip & Cohort Knee study were used. Six forms of health care services were described: analgesic use, supplement use, contact with a General Practitioner (GP), contact with a HP, contact in secondary care, and alternative medicine use. Multivariable logistic regression was performed in order to identify predisposing, enabling and disease-related variables that predict analgesic use and HP contact at 2 years; treatment modalities of first choice in early OA. RESULTS: For the hip (n=170), the knee (n=414) and the hip and knee (n=418) group analgesic use (38%, 29% and 47%, respectively), contact with a GP (32%, 38% and 36%, respectively) and contact with a HP (26%, 18% and 20%, respectively), were reported most often at baseline. Contact with a GP significantly decreased, supplement use increased (to about one third), and other treatment modalities remained stable at 2 years. In all three groups, analgesic use at baseline was the strongest predictor for analgesic use at 2 years, whereas contact with a HP at baseline was the strongest predictor of contact with a HP after 2 years. Belonging to a first generation minority was a predisposing risk factor [Odds Ratio (95%-CI), 8.72 (1.55-48.97)] for analgesic use in the hip and knee group. CONCLUSIONS: In early OA, familiarity with HCU and other predisposing factors are, apart from disease-related factors strongly associated with HCU at 2 years. Further research is necessary to examine whether our findings reflect sub-optimal management of early OA in terms of efficacy and equity.

A multidisciplinary and multidimensional intervention for patients with hand osteoarthritis.

BACKGROUND: Although several guidelines recommend that treatment programmes in patients with hand osteoarthritis should be both multidisciplinary and multidimensional, currently no such treatment programme for hand osteoarthritis has been described. Therefore the aim of this study was to systematically develop a multidisciplinary and multidimensional non-pharmacological treatment programme and to give a detailed description on the content of this treatment programme. DEVELOPMENT OF THE TREATMENT PROGRAMME: The programme was developed in phases. In a preclinical theoretical phase, disease-specific problems, current evidence and the influence of patient characteristics on the benefit of interventions were explored. In a modelling phase, the treatment programme was designed. TREATMENT PROGRAMME: The programme contains an individual intake, four weekly nurse and occupational therapist-led group sessions and a booster session after six months. Treatment components of the programme are self-management, daily home exercises to enhance joint mobility and grip strength and education about ergonomic principles. The treatment programme is tailored to the needs of individual patients with hand osteoarthritis. CONCLUSIONS: A non-pharmacological multidisciplinary and multidimensional treatment programme for patients with hand osteoarthritis was developed. Further research is necessary to investigate the effectiveness of this treatment programme. Currently, the programme is being evaluated in an ongoing randomized clinical trial.

Tailored cognitive-behavioural therapy and exercise training improves the physical fitness of patients with fibromyalgia.

OBJECTIVES: Patients with fibromyalgia have diminished levels of physical fitness, which may lead to functional disability and exacerbating complaints. Multidisciplinary treatment comprising cognitive-behavioural therapy (CBT) and exercise training has been shown to be effective in improving physical fitness. However, due to the high drop-out rates and large variability in patients' functioning, it was proposed that a tailored treatment approach might yield more promising treatment outcomes. METHODS: High-risk fibromyalgia patients were randomly assigned to a waiting list control group (WLC) or a treatment condition (TC), with the treatment consisting of 16 twice-weekly sessions of CBT and exercise training tailored to the patient's cognitive-behavioural pattern. Physical fitness was assessed with two physical tests before and 3 months after treatment and at corresponding intervals in the WLC. Treatment effects were evaluated using linear mixed models. RESULTS: The level of physical fitness had improved significantly in the TC compared with the WLC. Attrition rates were low, effect sizes large and reliable change indices indicated a clinically relevant improvement among the TC. CONCLUSIONS: A tailored multidisciplinary treatment approach for fibromyalgia consisting of CBT and exercise training is well tolerated, yields clinically relevant changes, and appears a promising approach to improve patients' physical fitness. ClinicalTrials.gov ID NCT00268606.

Cognitive-behavioral mechanisms in a pain-avoidance and a pain-persistence treatment for high-risk fibromyalgia patients.

OBJECTIVE: The heterogeneity of cognitive-behavioral patterns in patients with fibromyalgia (FM) has been proposed to underlie the variability in treatment outcomes. It has previously been shown that pain-avoidance and pain-persistence treatments tailored to the patient's pattern are effective in improving physical and psychological functioning and overall impact in high-risk patients with heightened psychological distress. In the present study, the cognitive-behavioral effects of these treatments were evaluated to provide insight into the main proposed mechanisms, specifically pain-avoidance behaviors and activity pacing in the pain-avoidance and pain-persistence treatments, respectively. METHODS: High-risk FM patients were classified into 2 groups, pain avoidance and pain persistence, and randomized in groups to the relevant treatment or waiting-list control condition. The pain-avoidance and pain-persistence treatments both comprised 16 twice-weekly sessions of cognitive-behavioral therapy and exercise training. Cognitive--behavioral factors assessed at pre- and posttreatment and 6 months of followup were evaluated using linear mixed models. RESULTS: A significant treatment effect was found for pain-avoidance behavior in the pain-avoidance treatment and for activity pacing in the pain-persistence treatment, showing improvements in the treatment condition relative to the controls. Furthermore, the effect on functioning was mediated by changes in pain-avoidance behavior in the pain-avoidance treatment and by changes in activity pacing in the pain-persistence treatment. Both treatments also showed significant improvements in other relevant cognitive-behavioral factors. CONCLUSION: Both the pain-avoidance and pain-persistence treatments are effective in improving cognitive-behavioral factors in high-risk FM patients. Pain-avoidance behavior and activity pacing might be important mediating mechanisms for beneficial outcomes in pain-avoidance and pain-persistence treatments, respectively.

Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible.

BACKGROUND: Many strategies, including intradermal vaccination, have been tested to augment antibody responses upon vaccination. This strategy has not been evaluated in different groups of immunocompromized patients. We conducted a prospective, randomized study to compare the humoral response upon standard intramuscular influenza vaccination with the response upon reduced-dose intradermal vaccination in patients treated with anti-tumor necrosis factor (TNF)-alpha, human immunodeficiency virus (HIV)-infected patients, hematologic stem cell transplantation (HSCT) patients, and healthy controls. METHODS: In total 156 immunocompromized patients and 41 healthy controls were randomized to receive either 0.5mL of the 2005/2006 trivalent influenza vaccine intramuscular or 0.1mL intradermal. Humoral responses, determined by hemagglutination inhibition assay, were measured before and 28 days postvaccination. Geometric mean titers (GMTs) and protection rates (PRs) are reported as primary outcomes, adverse events as a secondary outcome. RESULTS: Reduced-dose intradermal vaccination leads to similar GMTs and PRs, within all tested groups, compared to the standard intramuscular vaccination. Healthy controls yielded significantly better GMTs and PRs than immunocompromized patients. Local skin reactions after intradermal vaccination occurred less frequent and were milder in immunocompromized patients than in healthy subjects and were predictive for a positive vaccination outcome for individual subjects. CONCLUSIONS: Intradermal influenza vaccination is a feasible alternative for standard intramuscular vaccination in several groups of immunocompromized patients, including those treated with anti-TNF, HIV-infected patients and HSCT patients. The occurrence of a local skin reaction after intradermal vaccination is predictive of a response to at least one of the vaccine antigens.

CHECK (Cohort Hip and Cohort Knee): similarities and differences with the Osteoarthritis Initiative.

OBJECTIVE: To describe the osteoarthritis study population of CHECK (Cohort Hip and Cohort Knee) in comparison with relevant selections of the study population of the Osteoarthritis Initiative (OAI) based on clinical status and radiographic parameters. METHODS: In The Netherlands a prospective 10-year follow-up study was initiated by the Dutch Arthritis Association on participants with early osteoarthritis-related complaints of hip and/or knee: CHECK. In parallel in the USA an observational 4-year follow-up study, the OAI, was started by the National Institutes of Health, on patients with or at risk of symptomatic knee osteoarthritis. For comparison with CHECK, the entire cohort and a subgroup of individuals excluding those with exclusively hip pain were compared with relevant subpopulations of the OAI. RESULTS: At baseline, CHECK included 1002 participants with in general similar characteristics as described for the OAI. However, significantly fewer individuals in CHECK had radiographic knee osteoarthritis at baseline when compared with the OAI (p<0.001). In contrast, at baseline, the CHECK cohort reported higher scores on pain, stiffness and functional disability (Western Ontario and McMaster osteoarthritis index) when compared with the OAI (all p<0.001). These differences were supported by physical health status in contrast to mental health (Short Form 36/12) was at baseline significantly worse for the CHECK participants (p<0.001). CONCLUSION: Although both cohorts focus on the early phase of osteoarthritis, they differ significantly with respect to structural (radiographic) and clinical (health status) characteristics, CHECK expectedly representing participants in an even earlier phase of disease.

Screening for pain-persistence and pain-avoidance patterns in fibromyalgia.

BACKGROUND: The heterogeneity of patients regarding pain-related cognitive-behavioral mechanisms, such as pain-avoidance and pain-persistence patterns, has been proposed to underlie varying treatment outcomes in patients with fibromyalgia (FM). PURPOSE: To investigate the validity of a screening instrument to discriminate between pain-persistence and pain-avoidance patterns in FM. METHOD: In a three-part study, a self-reported screening instrument that assesses pain-avoidance behavior was used to distinguish patients with pain-persistence and pain-avoidance patterns. The resultant groups were compared with regard to several pain-related cognitive-behavioral factors, performance on a physical fitness test, and with regard to the judgments of trained therapists based on a semi-structured interview. RESULTS: The validity of the screening instrument to distinguish between pain-avoidance and pain-persistence patterns was supported by other validated self-report questionnaires for pain-related cognitive-behavioral factors, physical exercise tests, as well as by a high correspondence with blinded therapist judgment after intake assessments. CONCLUSION: These findings suggest that a short self-report screening instrument can be used to distinguish between pain-avoidance and pain-persistence patterns within the heterogeneous population of FM patients, which offers promising possibilities to improve treatment efficacy by tailoring treatment to specific patient patterns.

Tailored cognitive-behavioral therapy for fibromyalgia: two case studies.

OBJECTIVE: To illustrate a multidisciplinary group treatment for patients with fibromyalgia (FM) tailored to the patient's cognitive-behavioral pattern. METHOD: In a case-study design the tailored treatment approaches of two FM patients were described. One patient characterized by avoidance behavior (pain-avoidance pattern) participated in a group treatment aimed at changing pain-avoidance mechanisms and one patient characterized by continuing with activities in spite of pain (pain-persistence pattern) participated in a group treatment aimed at changing pain-persistence mechanisms. Assessments were made at baseline, post-treatment and at 6-months follow-up. RESULTS: Comparison of the pretest, post-test and follow-up scores on pain, functional disability, fatigue and psychological distress showed clinically significant improvements for both patients. CONCLUSION: The heterogeneity of patients regarding pain-related cognitive-behavioral mechanisms has been proposed to underlie varying treatment outcomes in FM patients. These results demonstrate that a group treatment tailored to pain-avoidance and pain-persistence patterns is feasible and can result in clinically significant changes for FM patients. PRACTICE IMPLICATIONS: FM offers a great challenge for clinicians due to the lack of effective treatment options. These case studies suggests that tailored CBT and exercise training directed at specific patient patterns can contribute to the improvement of the care of FM patients.

Generalized and symptom-specific sensitization of chronic itch and pain.

BACKGROUND: Physicians are frequently confronted with patients reporting severe itch and pain. Particularly in patients suffering from persistent itch and pain, central and peripheral sensitization processes are assumed to be involved in the long-term maintenance and aggravation of the symptoms. The present study explores generalized and symptom-specific sensitization processes in patients suffering from persistent itch and pain. Specifically, it examines whether patients with chronic itch and pain are more sensitive to somatosensory stimuli (generalized sensitization) and simultaneously perceive somatosensory stimuli as a symptom of their main physical complaint, e.g. pain in chronic pain patients (symptom-specific sensitization). METHODS: Thresholds for different mechanical and electrical sensory stimuli of Quantitative Sensory Testing were determined in 15 female patients suffering from chronic itch associated with atopic dermatitis, 15 female chronic pain patients diagnosed with fibromyalgia, and 19 female healthy controls. Intensities of itch and pain sensations were rated on a visual analogue scale. RESULTS: As expected, the patient groups had significantly lower tolerance thresholds for the somatosensory stimuli applied than the healthy controls, supporting generalized sensitization. Moreover, patients with chronic itch consistently reported more itch, while patients with chronic pain partly reported more pain in response to analogous somatosensory stimuli than the healthy controls and the other patient group, indicating symptom-specific sensitization. CONCLUSION: The present study provides preliminary support that both generalized and symptom-specific sensitization processes play a role in the regulation and processing of somatosensory stimulation of patients with chronic itch and pain.

Cognitive-behavioural therapies and exercise programmes for patients with fibromyalgia: state of the art and future directions.

This review provides an overview of the effects of non-pharmacological treatments for patients with fibromyalgia (FM), including cognitive-behavioural therapy, exercise training programmes, or a combination of the two. After summarising and discussing preliminary evidence of the rationale of non-pharmacological treatment in patients with FM, we reviewed randomised, controlled trials for possible predictors of the success of treatment such as patient and treatment characteristics. In spite of support for their suitability in FM, the effects of non-pharmacological interventions are limited and positive outcomes largely disappear in the long term. However, within the various populations with FM, treatment outcomes showed considerable individual variations. In particular, specific subgroups of patients characterised by relatively high levels of psychological distress seem to benefit most from non-pharmacological interventions. Preliminary evidence of retrospective treatment analyses suggests that the efficacy may be enhanced by offering tailored treatment approaches at an early stage to patients who are at risk of developing chronic physical and psychological impairments.

Serum levels of matrix metalloproteinase-3 in relation to the development of radiological damage in patients with early rheumatoid arthritis.

OBJECTIVE: To evaluate the significance of serum matrix metalloproteinase-3 (MMP-3) levels in relation to the development of radiological damage (X-ray damage) in early rheumatoid arthritis (RA). METHODS: Serum MMP-3 levels were measured in 46 healthy controls (CTRL), 19 osteoarthritis (OA) and 78 RA patients with joint symptoms for <1 yr at presentation (T0): 48 patients without and 30 with X-ray damage at T0. Serum MMP-3, measured by ELISA, and X-ray damage, scored according to Sharp's method, were assessed at 0, 6, 12 and 24 months. RESULTS: MMP-3 levels in CTRL and OA were low or undetectable with no differences between the groups (P=0.19). Levels in RA were higher than in CTRL (P<0.01). Initial MMP-3 levels in patients with X-ray damage at T0 (n=30) were higher than the levels in patients without any X-ray damage during follow-up (n=19) (P<0.01), but were not different from those in patients who developed X-ray damage during the study (n=29) (P=0.11). In the patients without X-ray damage at T0, there was a significant correlation between MMP-3 at T0 and the total X-ray damage after 6 months (r=0.34, P=0.02) and 12 months (r=0.32, P=0.03). This correlation was almost exclusively determined by joint space narrowing in the Sharp score. CONCLUSION: The serum MMP-3 level seems to be an indicator for the development of radiological damage in patients with early RA and appears to be particularly indicative of cartilage degradation.

Influence of a ceiling effect on the assessment of radiographic progression in rheumatoid arthritis during the first 6 years of disease.

OBJECTIVE: To evaluate at what disease duration and to what extent a ceiling effect, due to reaching maximum scores for erosions (E) and/or joint space narrowing (JSN) in separate joints, started to influence the assessment of radiographic progression according to the modified method of Sharp, in patients with recent onset rheumatoid arthritis (RA). METHODS: Prospective followup study of 87 patients with classical or definite RA, joint symptoms <1 year at study entry. Radiographs of hands and feet were made at study entry (Time 0), after 3 (T3), and after 6 years (T6) of followup. Assessment of radiographic progression according to the Van der Heijde modification of Sharp's method. The scores for E and JSN were analyzed separately in the individual groups of joints. Percentages of E joints, of joints with JSN, and of joints with maximum scores were assessed at T0, T3, and T6. The relative risks for the development of radiographic damage and of maximum scores were assessed for the individual joints. An approximation of the magnitude of the ceiling effect was calculated. RESULTS: After a disease duration of 6 years, a significant influence of a ceiling effect on the mean radiographic progression was found. In some individual patients the ceiling effect appeared to occur earlier. After 6 years, the maximum scores were distributed over 50% of the patients, and 20% of the patients had maximum scores in more than 10 joints without preference for specific localization. CONCLUSION: The ceiling effect appeared to be clinically relevant and should be taken into account when interpreting the effects of disease modifying antirheumatic drugs on radiographic progression in RA during the first years of the disease. Furthermore, it must be accounted for when describing the relationship between radiographic progression and process variables.

Phaeochromocytoma in various disguises.

Patients with phaeochromocytoma may present a broad spectrum of clinical manifestations as presented here in 5 case reports. Pathophysiology, clinical management, pharmacotherapy and associated diseases are discussed. Although catecholamine measurements in both urine and blood as well as modern localisation techniques are valuable adjuncts to establishing the diagnosis, a high index of suspicion remains the key to this diagnosis.

[Peripheral facial nerve palsy]. / Perifere nervus facialis-paralyse.

There are different etiological factors concerning the acute peripheral facial nerve palsy. In the majority of the cases, however, no etiological factor can be found. These cases are called idiopathic facial palsy or Bells palsy. Perhaps local anaesthetics could play a role as an etiological factor. By means of a case-report this form of facial nerve palsy will be discussed.

Anti-neutrophil cytoplasmic antibodies in giant cell arteritis and polymyalgia rheumatica.

Antineutrophil cytoplasmic antibodies (ANCA) were demonstrated in all sera from 11 patients with active giant cell arteritis (GCA) using indirect immunofluorescence on 9% paraformaldehyde(PF)-fixed neutrophils according to Pryzwanski (median titer 1:256, range 1:64 to 1:512). After treatment during inactive disease titers decreased in all sera. Eight out of 9 sera from patients with active polymyalgia rheumatica (PMR) produced a cytoplasmic staining on Pryzwanski-fixed neutrophils in low titers (median titer 1:16, range 0 to 1:32), as did 8 out of 25 sera from healthy blood donors. None of the sera were positive for antibodies to defined antigens, i.e. proteinase-3, human leucocyte elastase, myeloperoxidase and lactoferrin as detected by ELISA. GCA seems to be associated with ANCA of as yet unknown specificity.

Ciprofloxacin does not impair the elimination of diazepam in humans.

The pharmacokinetics of a single iv dose of 10 mg diazepam and the renal excretion of its metabolites resulting from N-demethylation and C-3-hydroxylation were investigated in 10 healthy volunteers when diazepam was administered alone and on day 3 of administration of the fluoroquinolone ciprofloxacin (500 mg twice per day). No significant changes in the diazepam half-life, its volume of distribution, the total body clearance, or the renal clearance were observed. In addition, the renal excretion of the metabolites desmethyldiazepam, 3-hydroxydiazepam (temazepam), and 3-hydroxydesmethyldiazepam (oxazepam) were not altered by ciprofloxacin co-medication. These data demonstrate that in a 500 mg twice per day oral dosage, ciprofloxacin does not influence the metabolic clearance of diazepam in young healthy volunteers.

[Epistaxis caused by an acquired thrombocytopathy]. / Epistaxis door verworven trombocytopathie.

Epistaxis may be the sole manifestation of a platelet aggregation dysfunction. Bleeding time according to Ivy within normal ranges does not exclude a severe disturbance of primary haemostasis. In two women (aged 53 and 76 yr, respectively) persistent epistaxis could not be stopped by local therapy. The bleeding time according to Ivy was within normal ranges in both cases. In one patient a bleeding disorder was not recognized as laboratory screening tests were normal and her situation became life-threatening. Anamnesis, clinical history and platelet aggregation tests led to the correct diagnosis; in one patient the relation with acetylsalicylic acid treatment was clear. After administration of platelet concentrate the bleeding stopped within a few hours in both cases and did not recur.